Three-dimensional regulatory hubs support oncogenic programs in glioblastoma. Academic Article uri icon

Overview

abstract

  • Dysregulation of enhancer-promoter communication in the three-dimensional (3D) nucleus is increasingly recognized as a potential driver of oncogenic programs. Here, we profiled the 3D enhancer-promoter networks of patient-derived glioblastoma stem cells to identify central regulatory nodes. We focused on hyperconnected 3D hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level and are associated with oncogenic programs that distinguish glioblastoma from low-grade glioma. Epigenetic silencing of a recurrent hub-with an uncharacterized role in glioblastoma-was sufficient to cause downregulation of hub-connected genes, shifts in transcriptional states, and reduced clonogenicity. Integration of datasets across 16 cancers identified "universal" and cancer-type-specific 3D hubs that enrich for oncogenic programs and factors associated with worse prognosis. Genetic alterations could explain only a small fraction of hub hyperconnectivity and increased activity. Overall, our study provides strong support for the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties.

publication date

  • March 21, 2025

Identity

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2025.03.007

PubMed ID

  • 40147440